Profiling of RNAs from Human Islet-Derived Exosomes in a Model of Type 1 Diabetes.

Preethi Krishnan,Raghavendra G Mirmira,Carmella Evans-Molina,Nicole Jiyun Kang,Farooq Syed

doi:10.3390/ijms20235903

Abstract

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing islet β cells. Biomarkers capable of identifying T1D risk and dissecting disease-related heterogeneity represent an unmet clinical need. Toward the goal of informing T1D biomarker strategies, we profiled coding and noncoding RNAs in human islet-derived exosomes and identified RNAs that were differentially expressed under proinflammatory cytokine stress conditions. Human pancreatic islets were obtained from cadaveric donors and treated with/without IL-1β and IFN-γ. Total RNA and small RNA sequencing were performed from islet-derived exosomes to identify mRNAs, long noncoding RNAs, and small noncoding RNAs. RNAs with a fold change ≥1.3 and a p-value <0.05 were considered as differentially expressed. mRNAs and miRNAs represented the most abundant long and small RNA species, respectively. Each of the RNA species showed altered expression patterns with cytokine treatment, and differentially expressed RNAs were predicted to be involved in insulin secretion, calcium signaling, necrosis, and apoptosis. Taken together, our data identify RNAs that are dysregulated under cytokine stress in human islet-derived exosomes, providing a comprehensive catalog of protein coding and noncoding RNAs that may serve as potential circulating biomarkers in T1D.

Highlights

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of the pancreatic β cells, resulting in the lifelong need for exogenous insulin treatment
Our results show that islet-derived exosomes express multiple classes of RNAs, with mRNAs being the most abundant class of long RNAs and micro RNAs (miRNAs) being the most abundant class among the known small noncoding RNAs
We identified 17,013 mRNAs and 5711 long noncoding RNAs (lncRNAs) from the total RNAseq protocol (Figure 4a), while 444 miRNAs, 175 piwi-interacting RNAs (piRNAs), 91 small nucleolar RNAs (snoRNAs), and 167 transfer RNAs (tRNAs) were identified from the small RNAseq protocol (Figure 4b)

Summary

Introduction

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of the pancreatic β cells, resulting in the lifelong need for exogenous insulin treatment. Over the past 30 years, considerable effort has been directed toward identifying therapies capable of inducing T1D remission and immune tolerance. An anti-CD3 monoclonal antibody (teplizumab) delayed the onset of T1D by approximately two years in high-risk individuals [5], providing support to the notion that T1D is a preventable disease. Despite these recent successes, T1D clinical trial efforts continue to be challenged by marked heterogeneity in treatment responses among study populations. There is significant heterogeneity in disease progression in autoantibody positive at-risk individuals, highlighting the need for improved methods to identify those who should be targeted with immunomodulatory interventions

Objectives

Methods

Results

Conclusion